[with update Nov. 25, 2013 at the end of the blog]
With colleagues Raymond De Vries (University of Michigan), Alice Dreger (Northwestern University), Lois Shepherd (University of Vriginia), Susan M. Reverby (Wellesley College) and Jerome P. Kassirer (Tufts University), I wrote a letter to the Chair, Vice-Chair and members of the University of Minnesota Senate, to request that the University of Minnesota set up an inquiry to investigate the circumstances surrounding the death of Dan Markingson in a clinical trial at the University of Minnesota Fairview Hospital. More than 170 leading academic colleagues specialized in health law and human rights, research ethics, bioethics, and medical research joined as signatories to the letter.
Dan Markingson was acutely psychotic when University of Minnesota psychiatrists enrolled him into an AstraZeneca-sponsored study of antipsychotic drugs. Prior to enrolling into the study, he had been repeatedly judged incompetent to make his own medical decisions and he was involuntary committed. He obtained a stay of commitment order that legally required him to obey the recommendations of the psychiatrists. They recommended he participate in a clinical trial, to which he was deemed able to consent, just days after he had been declared incapable of making his own treatment decisions. His mother, Mary Weiss, attempted to get her son out of the study for months, warning the research team that he was deteriorating and in danger of killing himself, but her warnings were ignored. On May 8, 2004, Markingson committed a violent suicide.
A 2009 investigation of Markingson’s death by the St. Paul Pioneer Press found that the university psychiatrists and the clinical trials unit had received significant payments from the study sponsor. The research contract included also a per patient payment of $ 15,648. Less than two years before Markingson was recruited, the Contract Research Organization in charge of organizing the trial had put the University of Minnesota site on 'probation' for failing to recruit a sufficient number of patients. With colleague Paul Miller, I have written in the past about how payments to investigators, particularly financial recruitment incentives, create significant legal and ethical concerns. This may very well be a case study of how some of the pressures resulting from these incentives can have a devastating outcome. For Dr. Jerome Kassirer, a former editor of the The England Journal of Medicine and a signatory of the letter, “[t]here was an overt conflict of interest, and there is reason to believe that the boy's death was an indirect consequence of the financial inducements of the study.”
In direct response to Dan Markingson’s suicide, the Minnesota legislature recognized already in 2009 that vulnerable psychiatric patients in Minnesota had to be better protected in clinical trials. It adopted more protective legislation, excluding people who are civilly committed from being enrolled in a clinical trial. In 2012, the Minnesota Board of Social Work concluded after an investigation that the study coordinator overseeing Markingson’s care had committed an alarming number of professional violations, including falsely initialing for the physicians on study charts and dispensing drugs without a license. The Board issued a “corrective action” towards the social worker. Those in charge of running the clinical trial, however, were not held accountable. The Minnesota Board of Medical Practice looked back in 2009 into complaints against the physicians supervising the clinical trial and involved in the care of Dan Markingson, Dr. Olson and Dr. Schulz, and contrary to the Board of Social Work, it concluded that it did not have a sufficient basis to take action.
We felt the need to write this letter because of the absence of a thorough and independent investigation into what happened. An FDA investigation, which focused on whether FDA procedures were followed, was arguably conducted only superficially, as Carl Elliott has convincingly put forward in a Hastings Center blog article. The FDA investigator failed, for example, to interview Dan Markingson’s mother and did not really address some of the key challenges in the context of this trial, such as those related to potential undue inducement and coercion. It concluded that no FDA regulations were violated. The University suggested that other internal reviews also came to the conclusion that no action was needed. But there are reasons to be worried about the independence of these assessments. The University's legal counsel suggested, for example, that the IRB--the institution's research ethics committee--had investigated the death. But so far, while minutes of one IRB meeting show that the case was discussed, no evidence of a solid IRB evaluation has been produced. There are also serious concerns about the independence of the IRB. First, it is questionable whether in-house IRBs can really act independently when important institutional interests are at stake and when high ranked institutional officials are involved. But more troubling is the recent revelation that the IRB that approved and was supposedly monitoring the clinical trial appears to have been affected by significant conflicts of interest. The IRB chair was the director of the ambulatory research center which housed the clinical trial; he also reported in the department of psychiatry to Dr. Schulz, chair of the department and co-investigator in the study; and he had financial relations with the company sponsoring the trial. Another internal University assessment which apparently took place can also hardly be characterized as an independent investigation, particularly since the University had dug its heels in the sand and took a strong position against further review of what happened. The University filed, for example, a ‘notice to assess costs’ against the mother of Dan Markingson, around the time that she wanted to appeal a partial summary judgment by a district court judge. With this notice, the University requested that she pay its legal expenses. The district court had ruled that there was no legal basis to sue the University and its IRB, since the IRB had statutory immunity for its ‘discretionary decisions’, but had accepted that a negligence claim against one of the doctors, Dr. Olson, could proceed. The University dropped this legal action for costs after Dan Markingson’s mother dropped her appeal against the interim decision.
In short: this appears to be a case that raises substantial concerns about the enrollment of extremely vulnerable and potentially incompetent research subjects in clinical trials, the appropriateness of specific informed consent and capacity assessment procedures in mental health research, the potential impact of financial conflicts of interest on the behavior of clinical investigators, university administrators, and institutional actors, the qualifications of research personnel, and the overall integrity of medical research at major medical schools and their hospitals. And it raises concerns about the legal tactics used by a public University in the context of a troubling case.
The signers of the letter include Susan Reverby, a historian, who uncovered the notorious Guatemala syphilis studies that led to a formal apology by President Obama in 2010; Marcia Angell of Harvard University, also a former editor of the New England Journal of Medicine; Richard Smith, a former editor of the British Medical Journal; Ron Patterson, the former Health and Disability Commissioner of New Zealand; George Annas, a leading Health Law and Human Rights scholar from Boston University; Daniel Callahan, the co-founder of The Hastings Center; Renee C. Fox, professor emeritus of the University of Pennsylvania and author of Experiment Perilous, one of the classic sociological texts on the ethics of medical research; several Canadian colleagues (including Nancy Olivieri, James Robert Brown, and Joel Lexchin of the University of Toronto; Laurence Kirmayer of McGill University; Jocelyn Downie, co-author of the CAUT Olivieri Report and Françoise Baylis, both Canada Research Chairs at Dalhousie University; Arthur Shafer, director of the Centre for Professional and Applied Ethics of the University of Mannitoba; Louis Charland of the University of Western Ontario; and Udo Schuklenk, Canada Research Chair at Queen's University) and various other leading scholars from the United States, Europe, Australia and New Zealand.
Various blogs and media reports have been raising concerns about the case in the past.
For more information on our action and on the case, see:
The media release about the letter
Pharmalot: Academics Want University to Probe a Suicide in Seroquel Trial
Edward Davies, in a recent article in the British Medical Journal
Jeremy Olsen & Paul Tosto, with a series of 4 articles in the St. Paul’s Pioneer Press. (Part 1, Part 2, PDF version of 4 parts)
A series of 6 articles by Judy Stone in the online Scientific American, with as first article "A Clinical Trial and Suicide Leave Many Questions: Part 1". [The 6 articles and additional articles on some specific aspects of the Markingson case can be found at the end of her November 25, 2013 blog post.]
Carl Elliott, of the University of Minnesota, in an article for Mother Jones, on the Bioethics Forum of the Hastings Center; and in various blog postings.
Matt Lamkin in a blog of Stanford Law School.
UPDATE November 25, 2013:
On November 12, 2013, we received a response from the General Counsel of the University of Minnesota to the letter we directed to the Chair and Vice-Chair of the University Senate, which confirms indirectly that the University appraoches this as a strict legal liability issue, not as an issue that raises important institutional ethics and governance issues. The counsel suggests in the letter that we might not be "completely familiar with the details of ... previous reviews conducted by a number of experts and governmental units independent of the University" and repeats earlier arguments that the case has been sufficiently investigated. We also learned that a University Senate subcommittee (the Faculty Consultative Committee) was discussing the Markingson case and our letter at one of its meetings, which could determine whether the full Senate will discuss our request for an Inquiry. The Minutes of that meeting are available online. We therefore sent a new letter, this time to the University Faculty Consultative Committee. The letter was accompanied by an updated list of signatories, and a schematic table which gives a clear overview of the various 'investigations' that the University alleges have taken place, and why we think that these investigations are insufficient or do not even amount to a real investigation.
For a new blog post by Judy Stone in Scientific American, discussing also other new developments, see: "What do the UMN and Disney have in Common?".
